Induction of intrinsic apoptosis in leukaemia stem cells and in vivo zebrafish model by betulonic acid isolated from Walsura pinnata Hassk (Meliaceae)

Leong, Kok Hoong; Mahdzir, Mohamad Azrul bin; Din, Mohd Fadzli Md; Awang, Khalijah; Tanaka, Yuka; Kulkeaw, Kasem; Ishitani, Tohru; Sugiyama, Daisuke

doi:10.1016/j.phymed.2016.12.018

Cited by 22 publications

(9 citation statements)

References 30 publications

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“…8), which could explain the result of our previous research [6]. There have been studies showing that betulonic acid and other LF triterpenoids could induce cancer cell apoptosis and cell cycle arrest via inhibiting PI3K/Akt pathway [65][66][67], which could also support the predicted mechanism.…”

Section: Go Enrichment Analysissupporting

confidence: 75%

Identification of the anti-breast cancer targets of triterpenoids in Liquidambaris Fructus and the hints for its traditional applications

Qian

et al. 2020

BMC Complement Med Ther

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Background Liquidambaris Fructus is the infructescences of Liquidambar formosana Hance and it has been used to treat some breast disease in Traditional Chinese Medicine. In the previous study we found the anti-breast cancer effect of triterpenoid in Liquidambaris Fructus. This study is a further investigation of the triterpenoids in Liquidambaris Fructus and aims to identify their anti-breast cancer targets, meanwhile, to estimate the rationality of the traditional applications of Liquidambaris Fructus. Methods Triterpenoids in Liquidambaris Fructus were isolated and their structures were identified by NMR spectrums. Potential targets of these triterpenoids were predicted using a reverse pharmacophore mapping strategy. Associations between these targets and the therapeutic targets of breast cancer were analyzed by constructing protein-protein interaction network, and targets played important roles in the network were identified using Molecular Complex Detection method. Binding affinity between the targets and triterpenoids was studied using molecular docking method. Gene ontology enrichment analysis was conducted to reveal the biological process and signaling pathways that the identified targets were involved in. Results Thirteen triterpenoids were identified and 6 of them were the first time isolated from Liquidambaris Fructus. Predicted ADME properties revealed a good druggability of these triterpenoids. We identified 18 protein targets which were closely related to breast cancer progression, especially triple-negative, basal-like or advanced stage breast cancers. The triterpenoids could bind with these targets as their inhibitors: hydrophobic skeleton is a favorable factor for them to stabilize at binding site and polar C17- or C3- substituent was necessary for binding. GO enrichment analysis indicated that inhibition of protein tyrosine kinases autophosphorylation might be the primary mechanism for the anti-breast cancer effect of the triterpenoids, and ErbB4 and EGFR were the most relevant targets. Conclusions The study revealed that triterpenoids from Liquidambaris Fructus might exert anti-breast cancer effect by directly inhibit multiple protein targets and signaling pathways, especially ErbB4 and EGFR and related pathways. This study also brings up another hint that the traditional applications of Liquidambaris Fructus on hypogalactia should be reassessed systematically because it might suppress rather than promote lactation by inhibiting the activity of ErbB4.

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Section: Go Enrichment Analysissupporting

confidence: 75%

Identification of the anti-breast cancer targets of triterpenoids in Liquidambaris Fructus and the hints for its traditional applications

Qian

et al. 2020

BMC Complement Med Ther

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“…The rounded canopy tree is 12 m to 37 m tall and is populates lowland rainforests [ 18 ]. Some triterpenes that have been isolated from dichloromethane extract of W. pinnata showed moderate cytotoxicity towards human breast cancer cells (MCF-7), human ovarian cancer cells (SK-OV-3) [ 19 ], and a good effect against leukaemia stem cells [ 20 ]. In a previous study of the hexane extract of W. pinnata bark, a cytotoxic effect against a human liver cancer (HepG2) cell line was seen at 50.00% inhibitory concentration (IC 50 ) value of 5.0 µg/mL [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Effects of Pinnatane A Extracted from Walsura pinnata (Meliaceae) on Human Liver Cancer Cells

et al. 2018

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Background: Pinnatane A from the bark of Walsura pinnata was investigated for its anti-cancer properties by analyzing the cytotoxic activities and cell cycle arrest mechanism induced in two different liver cancer cell lines. Methods: A 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to analyze the pinnatane A selectivity in inducing cell death in cancer and normal cells. Various biological assays were carried out to analyze the anti-cancer properties of pinnatane A, such as a live/dead assay for cell death microscopic visualization, cell cycle analysis using propidium iodide (PI) to identify the cell cycle arrest phase, annexin V-fluorescein isothiocyanate (annexin V-FITC)/PI flow cytometry assay to measure percentage of cell populations at different stages of apoptosis and necrosis, and DNA fragmentation assay to verify the late stage of apoptosis. Results: The MTT assay identified pinnatane A prominent dose- and time-dependent cytotoxicity effects in Hep3B and HepG2 cells, with minimal effect on normal cells. The live/dead assay showed significant cell death, while cell cycle analysis showed arrest at the G0/G1 phase in both cell lines. Annexin V-FITC/PI flow cytometry and DNA fragmentation assays identified apoptotic cell death in Hep3B and necrotic cell death in HepG2 cell lines. Conclusions: Pinnatane A has the potential for further development as a chemotherapeutic agent prominently against human liver cells.

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“…For example, ginsenoside Rg3, a triterpene saponin, inhibits CSCs of colorectal cancer [ 30 ] and gedunin, a natural tetranortriterpenoid, inhibits teratocarcinomal (NTERA-2) cancer stem-like cells [ 31 ]. The cucurbitacin E as a tetracyclic triterpene, betulonic acid, a pentacyclic lupane-type triterpenoid, and plant-derived triterpenoid tingenin B inhibit cervical cancer cell lines, leukemia stem cells, and breast CSCs, respectively [ 32 , 33 , 34 ]. Also, triterpene glycosides may be used as adjuvants for the rational design of vaccines against cancer [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Triterpene Acid (3-O-p-Coumaroyltormentic Acid) Isolated From Aronia Extracts Inhibits Breast Cancer Stem Cell Formation through Downregulation of c-Myc Protein

Choi

Kim

et al. 2018

IJMS

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Cancer stem cells (CSCs) are drug-resistant and radiation-resistant cancer cells that are responsible for tumor progression and maintenance, cancer recurrence, and metastasis. Targeting breast CSCs with phytochemicals is a new paradigm for cancer prevention and treatment. In this study, activity-guided fractionation from mammosphere formation inhibition assays, repeated chromatographic preparations over silica gel, preparatory thin layer chromatography, and HPLC using aronia extracts led to the isolation of one compound. Using 1H and 13C 2-dimensional nuclear magnetic resonance (NMR) as well as electrospray ionization (ESI) mass spectrometry, the isolated compound was identified as 3-O-p-coumaroyltormentic acid. This compound inhibits breast cancer cell proliferation and mammosphere formation in a dose-dependent manner and reduces the CD44high/CD24low subpopulation and aldehyde dehydrogenase (ALDH)-expressing cell population as well as the expression of the self-renewal-related genes CD44, SOX2, and OCT4. 3-O-p-Coumaroyltormentic acid preferentially reduced the protein levels of c-Myc, which is a CSC survival factor, by inducing c-Myc degradation. These findings indicate the novel utilization of 3-O-p-coumaroyltormentic acid for breast cancer therapy via disruption of c-Myc protein, which is a CSC survival factor.

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Induction of intrinsic apoptosis in leukaemia stem cells and in vivo zebrafish model by betulonic acid isolated from Walsura pinnata Hassk (Meliaceae)

Cited by 22 publications

References 30 publications

Identification of the anti-breast cancer targets of triterpenoids in Liquidambaris Fructus and the hints for its traditional applications

Identification of the anti-breast cancer targets of triterpenoids in Liquidambaris Fructus and the hints for its traditional applications

Cytotoxic Effects of Pinnatane A Extracted from Walsura pinnata (Meliaceae) on Human Liver Cancer Cells

Triterpene Acid (3-O-p-Coumaroyltormentic Acid) Isolated From Aronia Extracts Inhibits Breast Cancer Stem Cell Formation through Downregulation of c-Myc Protein

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